Severity Of Cartilage Lesions Research Articles

Effects of ovariectomy and estrogen therapy on type II collagen degradation and structural integrity of articular cartilage in rats: Implications of the time of initiation

To investigate how the time of initiation influences the effects of estrogen therapy on type II collagen (CII) turnover and the structural integrity of articular cartilage in ovariectomized rats and to determine whether estrogen exerts direct effects on the catabolic function of chondrocytes ex vivo. A total of 46 Sprague-Dawley rats were distributed into 1 of the following treatment groups: 1) ovariectomy, 2) ovariectomy plus early estrogen therapy, 3) ovariectomy plus delayed estrogen therapy, or 4) sham operation. Cartilage turnover was estimated by measuring the serum levels of C-telopeptide of type II collagen (CTX-II). Cartilage lesions at week 9 were quantified using a published scoring technique. The presence of the CTX-II epitope in articular cartilage was assessed by immunohistochemistry. The effects of estrogen (1-100 nM) on chondrocytes were investigated in bovine cartilage explants subjected to catabolic cytokines (tumor necrosis factor alpha [TNFalpha] and oncostatin M [OSM]). In ovariectomized rats, estrogen therapy evoked significant decreases in serum CTX-II independently of the time of initiation; yet, delayed initiation resulted in diminished efficacy in terms of preventing cartilage lesions. CTX-II fragments were present in articular cartilage, colocalizing with early lesions at the cartilage surface. In untreated animals, the early relative increases in serum CTX-II were proportional to the severity of cartilage lesions at week 9 (r = 0.73, P < 0.01). Estrogen significantly and dose-dependently countered CTX-II release from TNFalpha plus OSM-stimulated cartilage explants ex vivo. Our results suggest that estrogen counters the acceleration of CII degradation and related structural alterations, and these benefits can be maximized by early initiation after menopause. The protective effect of estrogen seems to involve direct inhibition of the catabolic function of chondrocytes.

Caspase inhibitors reduce severity of cartilage lesions in experimental osteoarthritis

To examine the therapeutic efficacy of caspase inhibitors in experimental osteoarthritis (OA). Experimental OA was induced in rabbits by anterior cruciate ligament transection (ACLT). Rabbits were treated with intraarticular (i.a.) injections of caspase inhibitors 3 times per week starting 1 week postoperatively. Animals were killed 9 weeks after ACLT, for macroscopic, histologic, and immunohistochemical assessment of the knee joints. I.a. administration of the pan-caspase inhibitor Z-VAD-FMK significantly reduced cartilage degradation, as assessed by macroscopic and microscopic criteria. Untreated knees showed large numbers of chondrocytes with active caspase 3 and the p85 fragment of poly(ADP-ribose) polymerase (PARP p85) that is generated during apoptosis. The frequency of cells positive for PARP p85 and active caspase 3 was reduced in Z-VAD-FMK-treated knees. Inhibitors specific for caspase 3 or caspase 8 showed no significant efficacy. Caspase 1 inhibitor and the combination of caspase 3 and caspase 8 inhibitors reduced OA pathology. These results provide direct support for a role of cell death in OA pathogenesis. Caspase inhibitors reduced the severity of cartilage lesions in experimental OA, suggesting that they may have disease-modifying activity in human OA.

Arthroscopic Débridement for Osteoarthritis of the Knee

The role of arthroscopic débridement in the treatment of osteoarthritis of the knee remains to be defined, and few clinical and radiographic characteristics have been quantitatively associated with the outcome. The hypothesis of this study was that the outcome of arthroscopic débridement for osteoarthritis of the knee is associated with preoperative clinical and radiographic features and intraoperative characteristics and that there are subsets of patients who are more and less likely to respond favorably to the treatment. We performed a cross-sectional study of a consecutive cohort of 122 patients who underwent arthroscopic débridement for the treatment of osteoarthritis of the knee that had been unresponsive to anti-inflammatory therapy. One hundred and ten patients were followed for a mean of thirty-four months. Pain was assessed with the pain domain of the Knee Society scoring system. Radiographs were scored with the Kellgren-Lawrence method, and limb alignment and the widths of the medial and lateral joint spaces were measured. The severity of cartilage lesions was scored intraoperatively with a modified Noyes grading system. Specific methods of data collection and analysis were incorporated to minimize bias. Fifty-two (90%) of fifty-eight knees with mild arthritis, normal alignment, and a joint space width of > or = 3 mm were improved after arthroscopic débridement. Conversely, only five (25%) of twenty knees with severe arthritis, limb malalignment, and a joint space width of < 2 mm had substantial relief of symptoms. Of seventy-two patients who had improvement, forty-four (61%) had it within six months after the arthroscopy. The severity of the lesion was highly predictive of the clinical outcome both in patients with mild arthritis and in those with severe arthritis. The severity of the arthritis, as assessed preoperatively with radiography and intraoperatively by rating the severity of cartilage lesions, influences the clinical outcome of arthroscopic débridement of an osteoarthritic knee. Knees with severe arthritis fare poorly, whereas those with mild arthritis fare well. We could not predict the outcome for knees with moderate arthritis. We believe that these observations are relevant for establishing indications for arthroscopy in patients with osteoarthritis of the knee and may be useful for designing studies with a more rigorous experimental design.

Myxobolus cerebralis infection patterns in Yellowstone cutthroat trout after natural exposure

Salmonid species and sub-species exhibit a range of susceptibility to Myxobolus cerebralis infection. Little is known about lesion severity and location, or time required for M. cerebralis myxospores to develop in Yellowstone cutthroat trout Oncorhynchus clarki bouvieri. In 2002 we performed three 10 d exposures of Yellowstone cutthroat trout fry in Pelican Creek, an M. cerebralis-positive tributary to Yellowstone Lake. At 90 and 150 d post-exposure we examined the fish for clinical signs, for infection prevalence, and by histology to determine M. cerebralis infection location and severity of lesions. The most prevalent clinical signs in Yellowstone cutthroat were whirling behavior and skeletal deformities, especially at 90 d post-exposure. Prevalence of infection and severity of cartilage lesions were not statistically different between fish held for 90 or 150 d post-exposure. Histopathology was most severe in cartilage of the cranium and the lower jaw, whereas cartilage of the nares and gill arches was seldom damaged. This study suggests that Yellowstone cutthroat trout are highly vulnerable to M. cerebralis and that current population declines in the Yellowstone Lake basin may, in part, result from whirling disease. Our results answer important questions in fish health and will aid in the development of diagnostic tools and management efforts against this pathogen in native cutthroat trout and other vulnerable salmonids.

Macroscopic and microscopic features of synovial membrane inflammation in the osteoarthritic knee: Correlating magnetic resonance imaging findings with disease severity

To determine the magnetic resonance imaging (MRI), macroscopic, and microscopic characteristics of synovial membrane inflammation, to study the relationship between disease severity and the degree of synovial inflammation on MRI and on macroscopic and microscopic examination, and to look for colocalization of chondral lesions and synovial inflammation. Thirty-nine patients with knee osteoarthritis (OA) were classified into 2 groups according to the severity of cartilage lesions as revealed by chondroscopy. Group 1 (n = 14) had mild cartilage lesion(s) without exposure of subchondral bone. Group 2 (n = 25) had severe cartilage lesion(s) with focal or diffuse exposure of subchondral bone. Synovitis was evaluated on T1-weighted MRI sequences according to the degree of synovial thickening on a 4-point scale (ranging from 0 to 3) in 5 regions of interest. Synovial membrane was macroscopically scored, and biopsies were performed on the 5 preselected sites for histologic scoring. The mean +/- SD synovial thickening score on MRI was 1.55 +/- 0.90, with no significant difference between groups 1 and 2. Intra- and interobserver reproducibility of the total synovial score was excellent, and interobserver reproducibility of the MRI grade was good. Synovitis was diffuse and associated with chondral lesions only in the medial femorotibial compartment (r = 0.49, P = 0.001). The degree of synovial thickening on MRI correlated with qualitative macroscopic analysis (r(s) = 0.58, P < 0.001) and with microscopic features (synovial lining cells [r(s) = 0.23, P < 0.007], surface fibrin deposition [r(s) = 0.12, P < 0.01], fibrosis [r(s) = 0.31, P < 0.006], edema [r(s) = 0.17, P = 0.07], congestion [r(s) = 0.30, P < 0.005], and infiltration [r(s) = 0.46, P < 0.0001]). Fibrin and infiltration parameters were more severe in end-stage disease (P = 0.009 and P = 0.02, respectively). Synovitis may be present from the onset of OA and may be evaluated on MRI. MRI evaluation of synovitis could be used to classify OA patients in clinical trials and could help to identify those who could benefit from synovium-targeted therapy.

Degenerative knee joint disease in mice lacking 3′-phosphoadenosine 5′-phosphosulfate synthetase 2 (Papss2) activity: a putative model of human PAPSS2 deficiency-associated arthrosis

Murine brachymorphism (bm) results from an autosomal recessive mutation of the Papss2 gene that encodes 3'-phosphoadenosine 5'-phosphosulfate synthetase 2, one of the principal enzymes required for the sulfation of extracellular matrix molecules in cartilage and other tissues. A spondyloepimetaphyseal dysplasia has been identified in Pakistani kindred having a mutation of PAPSS2. In addition to skeletal malformations that include short stature evident at birth due to limb shortening, brachydactyly, and kyphoscoliosis, affected individuals demonstrate premature onset degenerative joint disease. We investigated whether loss of Papss2 activity would similarly lead to degenerative joint disease in mice. Mice carrying the bm mutation on a C57BL/6 background were obtained from the Jackson Laboratory. Limbs were analyzed by micro-computed tomography (microCT) and histology. At 12 months of age both male and female bm mice exhibited severe degenerative knee joint disease, with cartilage damage being primarily evident in the patello-femoral and medial compartments. Control 12-14-month-old C57BL/6 mice, in contrast, only occasionally demonstrated minimal cartilage damage. muCT imaging of bm limbs revealed shortened diaphyses associated with flared metaphyses in the proximal elements of both fore and hind limbs. Additionally, the bm hind limbs demonstrated extensive structural alterations, characterized by distortion of the patello-femoral groove, and prominent bowing of both tibia and fibula. The bm mutant, which develops severe articular cartilage lesions of the knee joint by approximately 12 months of age, represents a novel example of murine degenerative joint disease, possibly representing a model of human PAPSS2 deficiency-associated arthrosis.

Pioglitazone, a peroxisome proliferator–activated receptor γ agonist, reduces the progression of experimental osteoarthritis in guinea pigs

To evaluate the in vivo therapeutic effect of pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, on the development of lesions in a guinea pig model of osteoarthritis (OA), and to determine the influence of pioglitazone on the synthesis of matrix metalloproteinase 13 (MMP-13) and interleukin-1beta (IL-1beta) in articular cartilage. The OA model was created by partial medial meniscectomy of the right knee joint. The guinea pigs were divided into 4 treatment groups: unoperated animals that received no treatment (normal), operated animals (OA guinea pigs) that received placebo, OA guinea pigs that received oral pioglitazone at 2 mg/kg/day, and OA guinea pigs that received oral pioglitazone at 20 mg/kg/day. The animals began receiving medication 1 day after surgery and were killed 4 weeks later. Macroscopic and histologic analyses were performed on the cartilage. The levels of MMP-13 and IL-1beta in OA cartilage chondrocytes were evaluated by immunohistochemistry. OA guinea pigs treated with the highest dosages of pioglitazone showed a significant decrease, compared with the OA placebo group, in the surface area (size) and grade (depth) of cartilage macroscopic lesions on the tibial plateaus. The histologic severity of cartilage lesions was also reduced. A significantly higher percentage of chondrocytes in the middle and deep layers stained positive for MMP-13 and IL-1beta in cartilage from placebo-treated OA guinea pigs compared with normal controls. Guinea pigs treated with the highest dosage of pioglitazone demonstrated a significant reduction in the levels of both MMP-13 and IL-1beta in OA cartilage. This is the first in vivo study demonstrating that a PPARgamma agonist, pioglitazone, could reduce the severity of experimental OA. This effect was associated with a reduction in the levels of MMP-13 and IL-1beta, which are known to play an important role in the pathophysiology of OA lesions.

Primary cartilage lesions and outcome among subjects with patellofemoral pain syndrome

We investigated the association between cartilage lesion and future symptoms in two groups of subjects with patellofemoral pain syndrome (PFPS). Group A consisted of 31 men (mean age 20.9 years, range 19-32) and group B of 28 consecutive patients (12 men and 16 women; mean age 27.8 years, range 15-50) operated on for PFPS. The mean follow-up time was 3.4 (range 1-7) years in group A and 4.9 (range 1-6) years in group B. At follow-up the subjects in group A with severe cartilage lesion (n = 10) reported more knee symptoms as measured by their Kujala score (mean 75.1, SE 3.6 vs. 88.5, SE 2.4) than those with minor cartilage lesion (n = 21) (age and follow-up time-adjusted P < 0.01). In group B the subjects with severe cartilage lesion tended to report more knee symptoms according to their Kujala score (mean 71.0, SE 7.0 vs. 86.1, SE 5.9; age, sex and follow-up time-adjusted P = 0.15) and VAS score (mean 51.8, SE 11.8 vs. 12.7, SE 10.4; adjusted P = 0.04) than the subjects without cartilage lesion. Our study shows that among the patients with PFPS, the subjects with severe cartilage lesion of the patella or femoral trochlea reported more subjective symptoms and functional limitations at follow-up than those without or with small cartilage lesion of the patella or femoral trochlea.

Primary Cartilage Lesions of the Knee Joint in Young Male Adults. Overweight as a Predisposing Factor. An Arthroscopic Study

This study was undertaken to evaluate the relationship between overweight and severity of arthroscopically confirmed primary cartilage lesions of the knee. The hospital records of 88 young male adults (98 knees), who underwent arthroscopy of the knee and were diagnosed of primary cartilage lesion during 1997-98, were reviewed. The depth of the lesions was graded according to Beguin and Locker classification. 73.5 % of the lesions were patellar and 12.0 % in the medial condyle of the femur. 74.5 % of the patients had superficial (grade I-II) and 25.5 % deep (grade III-IV) lesions. Patients with deep lesions had a significantly higher body mass index (BMI 25.3 vs. 22.9, p < 0.001) and they were older (20.8 vs. 19.7 years, p = 0.023) than other patients. Similarly, patients with overweight (BMI > or = 25.0) had significantly more often deep lesions than other patients (50 % vs. 10.4 %, p < 0.001). These results suggest, that overweight may predispose young patients to more severe cartilage lesions independent of other etiologic factors, and support the hypothesis of the cumulative effect of overweight on cartilage injuries during early adult life.

Accuracy of diagnostic arthroscopy for the assessment of cartilage damage in the equine metacarpophalangeal joint.

There are many noninvasive diagnostic methods used for evaluating chronic progressive joint disease, but each has severe limitations in the detection of early articular cartilage damage. To evaluate the accuracy of arthroscopy as a diagnostic method for the assessment of the severity of cartilage surface damage on the proximal articular margin of the equine first phalanx (P1). That arthroscopic assessment of the visible cartilage provides 1) a good indication of the integrity of the cartilage surface and 2) a good estimation of the status of the cartilage surface of the entire articular area of P1. Arthroscopic examination of the dorsal pouch of the metacarpophalangeal joint was performed in the left front limbs of 74 slaughter horses (age 5 months to 23 years). The appearance of the visible cartilage of P1 was scored by 2 independent arthroscopists, using the SFA arthroscopic grading system. The joints were dissected after completion of the arthroscopic procedure. The cartilage degeneration index (CDIP1) was determined and used as a quantitative measure for the overall degree of cartilage surface deterioration on the articular area of P1. Further, CDI values were determined for the dorsal articular margin of P1 (CDIdam), i.e. the area that can be visualised with arthroscopy. The CDIdam values were classified into 3 groups (CDIdam<25%, minor lesions; 25%<CDIdam<45%, moderate lesions; and CDIdam>45%, severe lesions). Differences between the 2 arthroscopists were evaluated statistically in a nonparametric test and Pearson correlation coefficients (r) with matching P values were determined for the correlations between SFA and CDIdam and between CDIP1 and CDIdam. The level of significance was set at P<0.05. Differences between SFA scores of the 2 arthroscopists were not significant (P = 0.22). In the group of joints with minor cartilage changes, there was no correlation between SFA and CDIdam (r = 0.12; P = 0.71), but there was a significant correlation between CDIP1 and CDIdam (r = 0.95; P<0.01). In the group with moderate cartilage damage, there was an increase in correlation between SFA and CDIdam (r = 0.27; P = 0.09) and a decrease in the correlation between CDIP1 and CDIdam (r = 0.48; P<0.01). In the group with severe cartilage changes, there was a significant correlation between SFA and CDIdam (r = 058; P<0.01), but no significant correlation between CDIP1 and CDIdam (r = 0.43; P = 0.06). Arthroscopic assessment of cartilage lesions on the proximal articular surface of P1 in joints with minor cartilage damage leads to an underestimation of the actual damage because proteoglycan depletion and light cartilage fibrillation cannot be detected arthroscopically. In cases with mild cartilage damage, the status of the cartilage surface of the visible area of P1 is a good representation of the status of the entire articular surface. In cases with severe cartilage lesions, there is an overestimation of real damage. In such joints, the arthroscopic scoring system provides reliable information, but the visible area is not representative of the entire articular surface. From a practical viewpoint, it can be stated that the arthroscopic grading of visible lesions on the equine P1 gives the best impression of overall cartilage damage in joints with moderately severe cartilage lesions. It should be realised, however, that this is the result of an underestimation due to the shortcomings of the grading system, which is neutralised by an overestimation due to the fact that the severity of lesions on the visible area of P1 is not representative for the entire articular surface.

Modification of osteoarthritis by pulsed electromagnetic field—a morphological study

Objective: Hartley guinea pigs spontaneously develop arthritis that bears morphological, biochemical, and immunohistochemical similarities to human osteoarthritis. It is characterized by the appearance of superficial fibrillation by 12 months of age and severe cartilage lesions and eburnation by 18 months of age. This study examines the effect of treatment with a pulsed electromagnetic field (PEMF) upon the morphological progression of osteoarthritis in this animal model. Design: Hartley guinea pigs were exposed to a specific PEMF for 1 h/day for 6 months, beginning at 12 months of age. Control animals were treated identically, but without PEMF exposure. Tibial articular cartilage was examined with histological/histochemical grading of the severity of arthritis, by immunohistochemistry for cartilage neoepitopes, 3B3(−) and BC-13, reflecting enzymatic cleavage of aggrecan, and by immunoreactivity to collagenase (MMP-13) and stromelysin (MMP-3). Immunoreactivity to TGFβ, interleukin (IL)-1β, and IL receptor antagonist protein (IRAP) antibodies was examined to suggest possible mechanisms of PEMF activity. Results: PEMF treatment preserves the morphology of articular cartilage and retards the development of osteoarthritic lesions. This observation is supported by a reduction in the cartilage neoepitopes, 3B3(−) and BC-13, and suppression of the matrix-degrading enzymes, collagenase and stromelysin. Cells immunopositive to IL-1 are decreased in number, while IRAP-positive cells are increased in response to treatment. PEMF treatment markedly increases the number of cells immunopositive to TGFβ. Conclusions: Treatment with PEMF appears to be disease-modifying in this model of osteoarthritis. Since TGFβ is believed to upregulate gene expression for aggrecan, downregulate matrix metalloprotease and IL-1 activity, and upregulate inhibitors of matrix metalloprotease, the stimulation of TGFβ may be a mechanism through which PEMF favorably affects cartilage homeostasis.

In vivo dual inhibition of cyclooxygenase and lipoxygenase by ML-3000 reduces the progression of experimental osteoarthritis: suppression of collagenase 1 and interleukin-1beta synthesis.

To study the therapeutic effectiveness of ML-3000, a new antiinflammatory drug that has balanced dual inhibitory activity against 5-lipoxygenase and cyclooxygenase, on the development of lesions in the experimental osteoarthritis (OA) dog model, and to determine the action of ML-3000 on the synthesis of collagenase 1 in cartilage and interleukin-1beta (IL-1beta) in synovial membrane. The anterior cruciate ligament of the right stifle joint of 21 mongrel dogs was sectioned with a stab wound. Dogs were divided into 3 groups: group 1 (n = 7) received placebo; groups 2 (n = 7) and 3 (n = 7) were treated with therapeutic dosages of oral ML-3000 at 2.5 mg/kg/day and 5 mg/kg/day, respectively. The dogs began receiving medication the day after surgery and were killed 8 weeks later. The size and grade of cartilage erosions on both the condyles and plateaus were evaluated, and the severity of the cartilage lesions and synovial inflammation was examined histologically. Levels of collagenase 1 in cartilage and IL-1beta in the synovial membrane were measured by immunohistochemistry. In addition, levels of prostaglandin E2 (PGE2) in the synovial fluid and leukotriene B4 (LTB4) in cultured synovial membrane explants were determined using specific enzyme immunoassays. Serum levels of ML-3000 in treated dogs were within the therapeutic range. ML-3000 significantly decreased the size and grade of the cartilage lesions in tibials and plateaus, compared with placebo. At the histologic level, the severity of cartilage lesions was also decreased in the ML-3000-treated dogs versus the placebo-treated dogs in both the condyles and the plateaus. All 3 OA groups exhibited a notable and similar level of synovial inflammation. ML-3000 significantly decreased the level of PGE2 in synovial fluid and LTB4 production by synovium. It also markedly reduced the levels of collagenase 1 in cartilage and IL-1beta in synovial membrane. ML-3000 significantly reduced the development of lesions in experimental dog OA. The drug acts by reducing the synthesis of the inflammation mediators PGE2 and LTB4 and catabolic factors such as collagenase 1 and IL-1beta, which are known to play an important role in the pathophysiology of OA lesions. The effect of the drug on catabolic factors could possibly be related to its inhibitory action on LTB4 synthesis.

Results of arthroscopic joint debridement in different stages of chondromalacia of the knee joint.

A retrospective study was performed of 161 patients who had undergone arthroscopic operation for chondromalacia of the knee joint. After an average follow-up period of 40 (range 10-72) months, patients with severe articular cartilage lesions who had undergone articular lavage alone showed significantly poorer results (P < 0.001). With the same stage of chondromalacia and having undergone the same surgical procedure, younger patients showed better results than older patients. The more effective interruption of the circulus vitiosus during the development of degenerative joint diseases is the primary cause for better results achieved by mechanical debridement of the joint for patients suffering from grade 2 or higher. According to the literature, aggressive subchondral abrasion in severely degenerated knees does not show any benefits. Apparently, the success of the therapy depends to a great extent on the inferiority of the potential degenerative regenerate (lack of capacity of intrinsic regeneration of the hyaline cartilage) as well as on the grade and the progression of chondromalacia. Almost every second patient suffering from grade 4 chondromalacia complained of recurrent pain 1 year postoperatively. One of every 6 patients received a knee joint prosthesis within the 1st year. Therefore, the patients' preoperative expectations have to be clearly objectified. The surgical procedure as an operation with a low complication risk can also be justified as a temporary alternative to total knee arthroplasty in patients suffering from a high-grade degeneration of the joint.

Slowly Progressive Osteoarthritis After Tibial Valgus Osteotomy in Young Beagle Dogs

A slowly progressive osteoarthritis model in the skeletally immature canine knee joint is described. Forty-four young female beagle dogs were chosen as experimental animals. In 15 dogs, a 30 degrees valgus angulation of the right tibia was created by operation. Fourteen dogs underwent sham operation. Fifteen dogs served as control subjects. Alterations in the knee joints were evaluated macroscopically and histologically 7 and 18 months after operation. Seven months after surgery, two of seven beagles that had valgus osteotomy had a lesion with discoloration of cartilage in the medial condyle of the femur. Eighteen months after operation, five of the eight dogs that had valgus osteotomy showed fibrillation of the femoral and tibial cartilages. Mankin's scoring of the knee joint cartilages indicated statistically significant changes as compared with control subjects 7 and 18 months after surgery. Biomechanical analysis revealed shift of the mechanical axis toward the lateral compartment of the knee by the valgus osteotomy, patellofemoral malalignment, and inclination of the tibiofemoral joint line. These biomechanical alterations brought about the most severe cartilage lesions to the medial condyle of the femur and the patellofemoral joint. Cartilage fibrillation took more than 7 months to develop. Thus, this model offers a slowly progressive, well standardized, and reproducible method for the study of early changes of osteoarthritis in young beagle dogs.

Effects of tenidap on the progression of osteoarthritic lesions in a canine experimental model. Suppression of metalloprotease and interleukin-1 activity.

To study, in vivo, the therapeutic effectiveness of tenidap, an antirheumatic drug, on the progression of lesions in an experimental osteoarthritis (OA) dog model. The action of tenidap on the activity and expression of metalloproteases in cartilage, as well as on the bioactivity of interleukin-1 (IL-1) in synovial fluid, was determined. The anterior cruciate ligament of the right stifle joint of 20 mongrel dogs was sectioned through a stab wound. Dogs were divided into 3 groups: group I (n = 7) received no treatment, group II (n = 6) was treated with oral omeprazole (20 mg/day), and group III (n = 7) received oral omeprazole (20 mg/day) and a therapeutic dosage of oral tenidap (3 mg/kg twice daily). Four weeks following surgery, the untreated dogs (group I) were killed, and drug treatments were begun for the other dogs (groups II and III). These dogs received medications for 8 weeks (weeks 4-12) and then were killed. Evaluations were made of the incidence and size of osteophytes as well as of the size and grade of cartilage erosions on both the condyles and plateaus. Histologic examination of the severity of the cartilage lesions and synovial inflammation was also performed. Activity levels of collagenase, stromelysin, and gelatinase as well as collagenase-1, collagenase-3, and stromelysin-1 messenger RNA were determined in the cartilage. The level of IL-1 activity in the synovial fluid was also measured. Among the dogs with OA, lesions were more severe at 12 weeks than at 4 weeks. Group III (tenidap-treated) dogs had a slightly reduced incidence of osteophytes compared with the group II (12-week OA) dogs (71% versus 100%), and the size of the osteophytes was significantly diminished (mean +/- SEM 1.75 +/- 0.69 mm versus 4.38 +/- 0.64 mm). Macroscopically, tenidap decreased the size (condyles 6.00 +/- 2.18 mm2 versus 21.08 +/- 6.70 mm2, plateaus 15.50 +/- 4.77 mm2 versus 35.0 +/- 3.64 mm2) and the grade (condyles 0.57 +/- 0.20 versus 1.17 +/- 0.21, plateaus 1.07 +/- 0.22 versus 2.00 +/- 0.25) of the cartilage lesions compared with the 12-week OA dogs. At the histologic level, the severity of cartilage lesions was also decreased in the tenidap-treated dogs versus the 12-week OA dogs, both on the condyles (3.43 +/- 0.54 versus 5.55 +/- 0.38) and on the plateaus (3.39 +/- 0.35 versus 5.54 +/- 0.60). All 3 OA groups showed a significant and similar level of synovial inflammation. Tenidap markedly decreased collagenase, stromelysin, and gelatinase activity, as well as the level of expression of collagenase-3 in the cartilage. Interestingly, the activity level of IL-1 in synovial fluid was also significantly reduced in the tenidap-treated dogs. Tenidap markedly reduced the severity of OA lesions, indicating the effect of this drug in decreasing the progression of disease. It appears that the drug acts by reducing the activity and/or expression of metalloproteases in cartilage, a process known to play a major role in the pathophysiology of OA lesions. This effect could be mediated by the suppressive effect of tenidap on IL-1 activity.

Chondroprotective effect of intraarticular injections of interleukin-1 receptor antagonist in experimental osteoarthritis. Suppression of collagenase-1 expression.

To investigate the in vivo effect of recombinant human interleukin-1 receptor antagonist (rHuIL-1Ra) on the development of lesions and the expression of metalloproteases in the canine experimental osteoarthritis (OA) model. The right anterior cruciate ligament was sectioned percutaneously in 3 groups of dogs. The control group (n = 5) received an intraarticular injection of sterile physiologic saline (1 ml) twice weekly for 4 weeks starting on the day of surgery. The remaining 2 groups received intraarticular injections of either 2 mg (n = 6) or 4 mg (n = 5) rHuIL-1Ra in 1 ml of physiologic saline according to the same schedule as the first group. All dogs were killed 4 weeks after surgery. The macroscopic appearance of femoral condyle osteophytes and the size and severity of cartilage lesions on femoral condyles and tibial plateaus were evaluated, as were the histologic features of cartilage and synovial membrane. Levels of collagenase-1 and stromelysin-1 messenger RNA expression in cartilage and synovium were determined by Northern blotting. Recombinant human IL-1Ra exerted a dose-dependent protective effect on the development of osteophytes and cartilage lesions in vivo. Treatment with rHuIL-1Ra reduced the incidence (saline-treated group 70%, 2 mg rHuIL-1Ra-treated group 42%, 4 mg rHuIL-1Ra-treated group 20%) and size (saline-treated group 2.3 +/- 0.7 mm [mean +/- SEM], 2 mg rHuIL-1Ra-treated group 0.7 +/- 0.3 mm, 4 mg rHuIL-1Ra-treated group 0.5 +/- 0.3 mm) of femoral condyle osteophytes. In addition, a dose-dependent decrease in the size (saline-treated group 24.40 +/- 8.17 mm2, 2 mg rHuIL-1Ra-treated group 20.90 +/- 8.01 mm2, 4 mg rHuIL-1Ra-treated group 7.70 +/- 5.16 mm2) and the grade (0-4 scale; saline-treated group 1.20 +/- 0.29, 2 mg rHuIL-1Ra-treated group 1.00 +/- 0.26, 4 mg rHuIL-1Ra-treated group 0.30 +/- 0.21) of the tibial plateau cartilage lesions was found, with a significant difference (P < 0.04) reached only with 4 mg rHuIL-1Ra. Similarly, the histologic lesions in dogs treated with 4 mg rHuIL-1Ra (Mankin scale; mean +/- SEM 2.95 +/- 0.53) were significantly less severe (P < 0.002) compared with those in the saline-treated group (4.95 +/- 0.54). Importantly, rHuIL-1Ra treatment led to a significant reduction (P < 0.005) of collagenase-1 expression in OA cartilage. This study demonstrated that intraarticular injections of rHuIL-1Ra can protect against the development of experimentally induced OA lesions. This effect could result, at least in part, from a reduction of collagenase-1 expression. However, other catabolic processes involved in the degradation of OA cartilage may also be affected.

Moderate exercise exacerbates the osteoarthritic lesions produced in cartilage by meniscectomy: a morphological study

Unilateral medial meniscectomy was performed on two groups of sheep. At 1 week post-operatively, one group (N = 5) underwent a regimen of moderate walking exercise (24 km/week), while the other group (N = 5) received no exercise. Two groups (N = 6 and 8) of unoperated sheep were used as exercised and unexercised controls for the respective meniscectomized groups. Six months post-surgery all groups were sacrificed and their knee joints were examined macroscopically using established scoring systems. In both groups, meniscectomy induced cartilage and bone changes typical of early hypertrophic osteoarthritis. However, meniscectomized animals subjected to the exercise program developed more severe cartilage lesions and osteophytes than their unexercised counterparts. While the cell density in femoral cartilage of the meniscectomized and exercised group was similar to controls, that of the meniscectomized but unexercised animals was higher. We conclude form these data that in this animal model exercise exacerbated the lesions induced in articular cartilage by meniscectomy.

Technic of synovectomy in the infected knee joint

In case of early diagnosis as well as correct indication and operation technique, synovectomy is an essential part in the treatment of an infected knee joint. The new formation of the synovia has been demonstrated by clinical/empirical as well as experimental studies, so that the alimentation of the cartilage can be normalized. Postoperative scarring due to adherence has to be prevented by continuous therapeutic exercises. In case of severe early infections, already existent severe cartilage lesions, and fibrous ankylosis, arthrodesis by means of external fixation is the method of choice. In these cases neither a healing of the infection nor a satisfactory function of the knee joint can be expected after the application of synovectomy.

Effects of intraarticular injection of halopredone diacetate on the articular cartilage of rabbit knees: A comparison with methylprednisolone acetate

Halopredone diacetate, which is a new synthetic corticosteroid drug showing local retention, and methylprednisolone acetate in common clinical use were injected into the knee joints of adult rabbits to compare the effects of the two drugs on the articular cartilage. The dosage of one injection was 1.75 mg (H-1 group) and 8.75 mg (H-5 group) for halopredone diacetate and 1.4 mg (M-1 group) and 7.0 mg (M-5 group) for methylprednisolone acetate. The drugs were injected into the right knee joint once a week, 12 times in total. One week after the last injection, the steroid crystals remaining in the knee joint were observed in all rabbits in the H-1 and H-5 groups. White deposits were seen locally on a part of the cartilage in all the rabbits in the H-1, H-5, and M-5 groups but not in the M-1 group. These white deposits were observed as cystic leisons by light microscopy and contained abundant hydroxyapatite. Other histologic findings in the articular cartilage included fissure, hypocellularity, and a decrease of proteoglycan in each group. However, no distinct difference was noted between the H-1 group and the M-1 group as regards the histological-histochemical grades of the cartilage on the medial tibial condyle or in the electron microscopic findings of the cartilage on the medial femoral condyle. The same was true for the H-5 and M-5 groups. These results show that repeated intraarticular injections of these two drugs cause severe cartilage lesions to the same degree, except for the intracartilaginous white deposits of rabbit knees.

EFFECTS OF AGE, BREED AND FLOOR TYPE ON THE INCIDENCE OF ARTICULAR CARTILAGE LESIONS IN PIGS

Articular cartilage lesions of a mild degree were observed in pigs shortly after weaning, indicating that the condition can occur in the very young pig. There were no significant differences (P &lt; 0.05) between breed or floor type in the incidence or severity of cartilage lesions. There were significant (P &lt; 0.05) increases in the incidence and severity of cartilage lesions with increasing weights of pigs, the largest increase occurring between 60 and 120 kg liveweight. The lesion score of the left proximal femur was the only joint lesion score significantly correlated with average daily gain. The highest incidence and severity of lesions occurred in the distal humerus and proximal femur. Levels of several blood serum constituents were not significantly correlated with the degree or severity of cartilage lesions. Mineralization of the compact bone appeared to be normal in pigs showing cartilage lesions, and there were no significant correlations between lesion score and bone mineral content.